Effect of a ketogenic diet versus Mediterranean diet on glycated hemoglobin in individuals with prediabetes and type 2 diabetes mellitus: The interventional Keto-Med randomized crossover trial

Abstract

Background: Consensus has not been reached on what constitutes an optimal diet in individuals with prediabetes and type 2 diabetes mellitus (T2DM), especially between low-carbohydrate options.

Objectives: We compared 2 low-carbohydrate diets with 3 key similarities (incorporating nonstarchy vegetables and avoiding added sugars and refined grains) and 3 key differences (incorporating compared with avoiding legumes, fruits, and whole, intact grains) for their effects on glucose control and cardiometabolic risk factors in individuals with prediabetes and T2DM.

Methods: Keto-Med was a randomized, crossover, interventional trial. Forty participants aged ≥18 years with prediabetes or T2DM followed the well-formulated ketogenic diet (WFKD) and the Mediterranean-plus diet (Med-Plus) for 12 weeks each, in random order. The diets shared the 3 key similarities noted above. The Med-Plus incorporated legumes, fruits, and whole, intact grains, while the WFKD avoided them. The primary outcome was the percentage change in glycated hemoglobin (HbA1c) after 12 weeks on each diet. Secondary and exploratory outcomes included percentage changes in body weight, fasting insulin, glucose, and blood lipids; average glucose from continuous glucose monitor (CGM), and nutrient intake.

Results: The primary analysis was of 33 participants with complete data. The HbA1c values did not differ between diets at 12 weeks. Triglycerides decreased more for the WFKD [percentage changes, -16% (SEM, 4%) compared with -5% (SEM, 6%) for the Med-Plus; P = 0.02] and LDL cholesterol was higher for the WFKD [percentage changes, +10% (SEM, 4%) compared with -5% (SEM, 5%) for the Med-Plus; P = 0.01]. Weight decreased 8% (SEM, 1%) compared with 7% (SEM, 1%) and HDL cholesterol increased 11% (SEM, 2%) compared with 7% (SEM, 3%) for the WFKD compared with the Med-Plus, respectively; however, there was a significant interaction of diet × order for both. Participants had lower intakes of fiber and 3 nutrients on the WFKD compared with the Med-Plus. Twelve-week follow-up data suggest the Med-Plus is more sustainable.

Conclusions: HbA1c values were not different between diet phases after 12 weeks, but improved from baseline on both diets, likely due to several shared dietary aspects. The WFKD led to a greater decrease in triglycerides, but also had potential untoward risks from elevated LDL cholesterol and lower nutrient intakes from avoiding legumes, fruits, and whole, intact grains, as well as being less sustainable. This trial was registered at clinicaltrials.gov as NCT03810378.

Keywords: HbA1c; Mediterranean; diabetes; diet; human; intervention; ketogenic; metabolomic; prediabetes.

FIGURE 1

(A) Keto-Med randomized trial study design. *CGM worn for a 2-week interval at each time, as indicated by the square borders. (B) Key similarities and differences for the 2 Keto-Med diet patterns. Abbreviations: CGM, continuous glucose monitoring; Med-Plus, Mediterranean-plus diet; WFKD, well-formulated ketogenic diet.

FIGURE 2

Consolidated Standards of Reporting Trials participant flow for the Keto-Med randomized trial. Abbreviations: CGM, continuous glucose monitoring; COVID-19, coronavirus disease 2019; HbA1c, glycated hemoglobin; PreD, prediabetes; T2DM, type 2 diabetes mellitus.

FIGURE 3

Percent change from baseline by diet (n = 33). Presented by diet (the WFKD compared with the Med-Plus), median (square), and IQR (bars) of percentage changes from baseline in HbA1c, fasting glucose, fasting insulin, fasting LDL cholesterol, fasting HDL cholesterol, fasting triglycerides, fasting ALT, and weight (including some self-reported weight changes during COVID-19). Also, P values (above) from a likelihood ratio test for diet show differences in a linear, mixed-effect model after adjusting for order, diabetes status, and correlated observations. *Significant interaction effect of diet × order (P < 0.05). Abbreviations: ALT, alanine aminotransferase; COVID-19, coronavirus disease 2019; HbA1c, glycosylated hemoglobin; Med-Plus, Mediterranean-plus diet; WFKD, well-formulated ketogenic diet.

FIGURE 4

Weight change from baseline by phase and diet order (n = 33). The only time point at which the weight loss difference was significant was at week 12, at the end of the first diet phase, with a mean difference of 6.9 kg (SEM, ±0.8 kg) compared with 5.0 kg (SEM, ±0.80 kg) for the WFKD and Med-Plus, respectively (P = 0.04; paired t-test). Abbreviations: Med-Plus, Mediterranean-plus diet; WFKD, well-formulated ketogenic diet.